The long-term objective of this proposal is to study the relationship between the aging process, neurodegenerative diseases of aging, and neurotoxic exposure. The specific aims of this project are designed to test the hypotheses that exogenous exposure to a neurotoxin can result in a neurodegenerative disorder that (1) may occur on a delayed basis and (2) may be progressive in nature. The project represents a 5-year cohort study of a well-defined group of 81 humans, who, based on operationally defined and empirically validated criteria, were exposed to a neurotoxin that is known to cause degeneration of neurons in the substantia nigra (the same area of a neurotoxin that is affected in Parkinson's disease); these individuals are currently either mildly affected, to have no clinical evidence of parkinsonism. This cohort, along with a comparison group of 30 comparable but unexposed individuals, will be evaluated annually using four neurologic assessment measures (the Unified Parkinson's Disease Rating Scale [UPDRS] Motor Examination, Hoehn and Yahr staging, the neuropsychological assessments (Stroop Word-Color Test and the Category Naming Test); examiners will be masked as to exposure history. Position emission tomography (PET) will be performed biannually to assess striatal dopamine content. If it is found that a neurotoxic insult can induce a progressive degenerative disease months or even years after exposure, it could provide important clues as to the cause of Parkinson's disease, as well as other neurodegenerative disease of aging. Further, if either PET or neuropsychological tests prove to have predictive value regarding the onset of parkinsonism, it could lead to a new therapeutic strategy aimed at preventing Parkinson's disease, since several agents are currently being tested to see if they slow or halt disease progression.